title: Preventive effects of (-)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db Mice.
abstract: Obesity and related metabolic abnormalities, including insulin resistance and a state of chronic inflammation, increase the risk of hepatocellular carcinoma. Abnormal activation of the insulin-like growth factor (IGF)/ IGF-1 receptor (IGF-1R) axis is also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of (-)-epigallocatechin gallate (EGCG), a major biologically active component of green tea, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks and then they received drinking water containing 0.1% EGCG for 34 weeks. At sacrifice, drinking water with EGCG significantly inhibited the development of liver cell adenomas in comparison with the control EGCG-untreated group. EGCG inhibited the phosphorylation of the IGF-1R, ERK (extracellular signal-regulated kinase), Akt, GSK-3β (glycogen synthase kinase-3β), Stat3, and JNK (c-Jun NH(2)-terminal kinase) proteins in the livers of experimental mice. The serum levels of insulin, IGF-1, IGF-2, free fatty acid, and TNF-α were all decreased by drinking EGCG, which also decreased the expression of TNF-α, interleukin (IL)-6, IL-1β, and IL-18 mRNAs in the livers. In addition, EGCG improved liver steatosis and activated the AMP-activated kinase protein in the liver. These findings suggest that EGCG prevents obesity-related liver tumorigenesis by inhibiting the IGF/IGF-1R axis, improving hyperinsulinemia, and attenuating chronic inflammation. EGCG, therefore, may be useful in the chemoprevention of liver tumorigenesis in obese individuals. Cancer Prev Res; 4(3); 396-403. ©2011 AACR.
authors.affiliation: Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. shimim-gif@umin.ac.jp
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakai
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shirakami
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Daishi
authors.initials: D
authors.lastname: Terakura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Baba
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohno
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hara
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
mesh_terms: D000236:Adenoma / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D002273:Carcinogens; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D004052:Diethylnitrosamine / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D005230:Fatty Acids, Nonesterified; D004052:Diethylnitrosamine; D002392:Catechin; C045651:epigallocatechin gallate; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases